A Phase I Clinical Study of High Dose Ketoconazole Plus Weekly Docetaxel for Metastatic Castration Resistant Prostate Cancer
A Phase I Clinical Study of High Dose Ketoconazole Plus Weekly Docetaxel for Metastatic Castration Resistant Prostate Cancer
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DOI：
10.1016/j.juro.2010.02.020
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发表时间：
2010-06-01
影响因子：
6.6
通讯作者：
Dahut, William L.
中科院分区：
文献类型：
--
作者：
Figg, William D.;Woo, Sukyung;Dahut, William L.
目的：大剂量酮康唑联合多西紫杉醇治疗去势耐受前列腺癌的I期研究，旨在确定联合应用多西紫杉醇和酮康唑的最大耐受量、副作用和药代动力学相互作用。材料和方法：转移性去势耐受前列腺癌患者每周服用多西他赛，每4周3次，每日1次酮康唑。在第1天(单用多西他赛)和第16天(用酮康唑后)进行了药代动力学研究。结果：这项研究纳入了9个不同剂量水平的42名患者。研究的联合方案包括多西他赛每周一次，从5 mg/m~2增加到43 mg/m(2)，起始量分别为600、800或1200 mg/d。62%的患者前列腺特异性抗原下降50%或更多。在25例软组织病患者中，7例(28%)有部分反应。中位总生存期为22.8月，多西紫杉醇初治患者的中位生存期显著高于多西紫杉醇治疗前的患者(36.8vs10.3个月，p=0.0001)。最常见的不良反应是贫血、浮肿、疲劳、腹泻、恶心、感觉神经病变和肝功能升高。多西紫杉醇清除量的变化分数与酮康唑暴露显著相关(p
Purpose: This phase I study of high dose ketoconazole and docetaxel was designed against castration resistant prostate cancer to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of co-administered docetaxel and ketoconazole.Materials and Methods: Patients with metastatic castration resistant prostate cancer received weekly docetaxel for 3 of every 4 weeks plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole).Results: The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly, increasing from 5 to 43 mg/m(2), with starting doses of 600, 800 or 1,200 mg ketoconazole daily. Decreases in prostate specific antigen of 50% or greater were seen in 62% of patients. Of 25 patients with soft tissue disease 7 (28%) had a partial response. Median overall survival was 22.8 months and was significantly greater in docetaxel naive patients than in patients pretreated with docetaxel (36.8 vs 10.3 months, p = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (p